Abstract

Infectious bronchitis virus, otherwise known as
coronavirus, can cause mild upper respiratory tract illnesses in
children and adults. Rarely has coronavirus been linked, either by
serology or nasal wash, to pneumonia. We report a case of a young woman
who, following treatment for stage IIIA breast cancer using a high-dose
chemotherapy regimen followed by autologous bone marrow and stem cell
transplantation, developed respiratory failure and was found to have
coronavirus pneumonia as diagnosed by electron microscopy from BAL
fluid. We propose that coronavirus should be considered in the
differential diagnosis of acute respiratory failure in cancer patients
who have undergone high-dose chemotherapy and autologous hematopoietic
support.

Figures in this Article

Interstitial
pneumonitis is a frequent complication following high-dose chemotherapy
and autologous bone marrow transplantation
(HDC/ABMT).1,,2 Infectious etiologies have been identified
in about 50% of cases and include cytomegalovirus (CMV), herpes
simplex virus, respiratory syncytical virus (RSV), Pneumocystis
carinii, adenovirus, Aspergillus, and Candida.,1,,2 In
the remaining cases in which no infectious agents could be identified,
several distinct syndromes have been described. Idiopathic pneumonia
syndrome (IPS) is the most severe form of posttransplant interstitial
pneumonitis and is best characterized by severe hypoxemia, radiographic
infiltrates, and is associated with high mortality.3,,4,,5
However, we have recently described in detail a milder form of
posttransplant pneumonitis occurring in autologous bone marrow
transplant (BMT) patients that we have termed delayed pulmonary
toxicity syndrome (DPTS).6 DPTS is characterized by its
high incidence (69%), prompt response to steroids with resolution of
pulmonary symptoms and improvement in diffusion of carbon monoxide
(Dlco), and very low mortality.,6,,7
Radiographic abnormalities, when present, typically appear as
scattered, predominantly peripheral ill-defined
opacities.8

Possible mechanisms for the pathogenesis of either IPS or DPTS
include the following: (1) pulmonary drug toxic reactions caused by
carmustine (BCNU) and/or cyclophosphamide;3,,9 (2)
imbalance of lung cytokines that promote a proinflammatory
state;10,,11 (3) occult latent viral infections
(eg, CMV, RSV, Epstein-Barr virus, or human herpes 6
virus);,12,,13 or (4) an imbalance in pulmonary oxidants and
antioxidants.14 Allogeneic transplant patients, in
contrast to autologous, are also susceptible to graft-vs-host disease
processes and in addition, are maintained in an immunodeficiency state
for an extended time.

The coronaviruses are one of the more recently identified major
family of viruses that have been associated with the development of the
common cold. They are a family of positive-sense single-stranded RNA
viruses with distinctive club-shape projections imparting a crown or
corona-shaped appearance. OC43 and 229E are two major serologic
coronavirus strains identified to be important in human
disease.15,,16,,17 Only indirectly has coronavirus been linked
to lower respiratory tract infections.18,,19,,20

In this report, we document the development of acute respiratory
failure following BMT that was atypical of either IPS or DPTS and that,
we believe, was caused or exacerbated by coronavirus pneumonia. To our
knowledge, this represents the first reported case of coronavirus
isolated from lower respiratory tract specimens in an adult with
pneumonia.

Case Report

A 35-year-old Jamaican woman, 155 days post HDC/ABMT for stage
IIIA breast carcinoma, was admitted to Duke University Hospital with
complaints of fatigue, anorexia, and weight loss and for further workup
of hyperbilirubinemia.

The patient had been well until 13 months prior to hospital
admission when a left breast mass was noted on self-examination. An
incisional biopsy specimen with subsequent modified radical mastectomy
revealed an infiltrating ductal carcinoma with 14/15 lymph nodes
positive for metastatic tumor. A staging chest/abdomen/pelvis/head CT
and bone scan revealed no metastatic disease. Results of initial
laboratory studies, including liver function tests, were normal.
Baseline pulmonary function testing demonstrated an FEV1 of
2.27 L/s (76%), FVC of 2.79 L (80%), total lung capacity of 3.46 L
(71%), and a hemoglobin-corrected Dlco of 28.5 (mL/min/mm
Hg) (133%).

The patient was enrolled on Cancer and Leukemia Group B
protocol 9082. She received four cycles of CAF
(cyclophosphamide, 600 mg/m2 on day 1, doxorubicin, 60
mg/m2 on day 1, and fluorouracil, 600 mg/m2 on
days 1 and 8) given every 28 days (Fig 1)
that was followed by high-dose CPA/CDDP/BCNU (cyclophosphamide [1,875
mg/m2], given IV over 1 h each of three consecutive
days (day −6, −5, −4), cisplatin [55 mg/m2] given by
continuous infusion over 24 h each day for days −6, −5, and −4,
and BCNU [600 mg/m2] infused over 2 h on day −3).
The total plasma area under the curve for cyclophosphamide was
93,280 μg/mL × min. Cisplatin levels were determined at the end of
each 24-h dose and were 112.4, 62.8, and 121.6 ng/mL. The BCNU plasma
area under the curve was 607.5 μg/mL × min. Two days following
high-dose chemotherapy, peripheral blood progenitor cells were
reinfused (days −1, 0, +1) and autologous bone marrow
(0.7 ± 0.25 × 108 cells per kilogram of body weight)
was reinfused on day +1 to provide cellular support. Engraftment was
uneventful and occurred by 2 weeks.

Thirty-eight days post-BMT, the patient developed over the
course of 2 days, a nonproductive cough and dyspnea. An arterial
blood gas determination performed on room air showed a pH of 7.45,
Pco2 of 36 mm Hg, Po2
of 89 mm Hg, and O2 saturation of 98%. Pulmonary function
testing at this time showed that her Dlco had fallen 54%
from her baseline level (Fig 1). Based on these findings, she was
diagnosed as having DPTS and was started on a regimen of oral
prednisone at 60 mg/d. In addition, prophylactic oral
trimethoprim/sulfamethoxazole was prescribed. She responded to
prednisone treatment with prompt resolution of her pulmonary symptoms
and a modest improvement of 11% in her Dlco.

At 83 days post-BMT, routine blood testing demonstrated mildly
elevated results of liver function tests. At 91 days, her chest wall
and regional node radiation therapy was begun and continued over 6
weeks for a total dose of 60.4 Gy.

At 157 days post-BMT, the patient was admitted to the hospital for
workup of persistent hyperbilirubinemia. Percutaneous liver biopsy
specimens demonstrated severe, centrilobular cholestasis with plugs in
canaliculi consistent with centrilobular canalicular and hepatocellular
cholestasis. This was believed to be consistent with an idiosyncratic
drug reaction. Later that evening, she developed a brief episode of
hypotension and complained of right shoulder pain. Abdominal CT
demonstrated a small right subcapsular hematoma at the site of the
liver biopsy. On hospital day 3, the patient spiked a fever with a
temperature of 38.9°C. Blood and urine cultures were sent to the
laboratory and the patient was started on a regimen of oral
clarithromycin. At about this time, she complained of a sore throat and
a new cough, slightly productive of sputum. A nasal swab was negative
for RSV, parainfluenza A, B, and C, adenovirus, and influenza A and B.
Results of pulmonary function testing were unchanged from 13 days
previously (Fig 1).

On hospital day 4, the patient was noted to be tachypneic with a
respiratory rate in the 40s. An arterial blood gas determination
obtained on room air showed a pH of 7.46, Pco2
of 25, Po2 of 36, and O2 saturation
of 70%. An echocardiogram demonstrated normal ventricular function.
Despite a 3-L diuresis, the patient’s respiratory status continued to
deteriorate and she was electively intubated. Because of concerns of
recurrent DPTS, the patient was started on a regimen of high-dose
methylprednisolone at 60 mg IV every 6 h. Erythromycin,
sulfamethoxazole and trimethoprim (Bactrim), and imipenem were added
empirically. A portable chest radiograph and chest CT scan demonstrated
bilateral, predominantly lower lobe air space opacities (Fig 2).

On hospital day 6, the patient underwent bronchoscopy and a BAL of both
lower lobes was obtained via the endotracheal tube. Microbiological
examination demonstrated the BAL sample to be negative for fungus,
acid-fast bacilli, Gram stain and culture, cytology with special
stains, respiratory viral battery (RSV, parainfluenza A, B, and C,
adenovirus, and influenza A and B), CMV, and herpes simplex virus
culture. Cytologic analysis showed rare atypical cells on a background
of highly reactive pneumocytes. Electron microscopy (EM) of the BAL
fluid demonstrated numerous viral particles with features that were
diagnostic of coronavirus (Fig 3).

On hospital day 7, treatment with all antibiotics was stopped
and the patient had completely defervesced. On hospital day 8,
the patient was successfully extubated. By hospital day 10, she was
breathing room air with on oxygen saturation of 96%. Her steroids were
changed to prednisone at 60 mg to be tapered over 6 to 8 weeks. On
hospital day 12, she was discharged to home. A follow-up visit at
post-BMT day 220 showed her Dlco to be decreased
approximately 21% from her prehospitalization value (Fig 1). However,
her respiratory status remained asymptomatic.

Discussion

The incidence of pulmonary toxic reactions following high
doses of cyclophosphamide/cisplatin and BCNU with autologous bone
marrow support in the Duke University Bone Marrow Transplant Program is
approximately 39 to 69%.6,,7,,21 Most patients in whom
infection is ruled out have a low mortality rate and a prompt response
to prednisone therapy. Because of these features, we have termed this
posttransplant complication DPTS.6 DPTS is to be
contrasted to IPS, a syndrome characterized by severe hypoxemia,
radiographic infiltrates, and high mortality.4

Our patient demonstrated three phases of pulmonary toxic reactions.
Phase I is subclinical and asymptomatic and is best characterized by a
decreased Dlco measurement following the first three cycles
of the CAF induction chemotherapy (Fig 1). Little is known about the
contribution that the conditioning regimen plays in the development of
lung injury.

Phase II occurred following HDC/ABMT and was diagnosed as DPTS based on
its timing, associated pulmonary symptoms, decrease in
Dlco, and prompt response to corticosteroid therapy with
subsequent improvement in Dlco.

Phase III occurred approximately 158 days following BMT when the
patient developed acute respiratory failure. Was coronavirus pneumonia
responsible for her respiratory failure? We believe so. The BAL sample
was obtained 36 h after intubation and the bronchoscope was placed
into the lumen of the endotracheal tube, thus minimizing possible nasal
mucosa contamination. We have considered other possibilities. For
example, the coronavirus could simply have been present in the BAL
specimen, but was not pathogenic. In this scenario, the etiology of the
respiratory failure could have been caused by several different
factors, including radiation pneumonitis, drug-induced interstitial
pneumonitis, or showering of the lung with inflammatory cytokines from
an abdominal or septic source resulting in ARDS. Radiation pneumonitis
seems less likely since the pattern of radiographic lung injury does
not duplicate the radiation port,6 although case studies
have shown that radiation pneumonitis can occur outside the radiation
port.22 It would be unusual to see interstitial
pneumonitis from the HDC/ABMT this far out after transplant and without
a concomitant decrease in Dlco.,6 The liver
biopsy, which occurred 2 days before respiratory failure, was
complicated by a stable subcapsular hematoma, a brief episode of
hypotension, and fever. We cannot exclude the possibility that
inflammatory cytokines, released from GI sources, showered the lung
causing acute lung injury leading to respiratory failure. Also, we
could not rule out bacterial pneumonia as a complicating factor since
the patient was receiving antibiotics for >24 h prior to obtaining BAL
fluid and this would be predicted to lower our diagnostic yield of
bacteria.

Can coronavirus cause lower respiratory tract infection? Animal strains
of coronavirus appear more virulent than their human counterparts and
have been shown to cause pneumonia in mice and pigs.23,,24
In humans, experimental intranasal inoculation of coronavirus in
volunteers results in a typical coryzal illness with nasal discharge
and a notable absence of systemic complaints.25,,26,,27
However, lower respiratory tract involvement has been suggested based
on coronavirus positive nasal washes in two children with
pneumonia18and by coronavirus seroconversion in adults
who had pneumonia.19,,20 Treatment options for upper
respiratory tract infection caused by coronavirus are limited, but
studies using intranasal interferon α-2b28,,29 and
intranasal nedocromil30 improve symptoms.

We discovered coronavirus in this patient because the BAL specimen was
evaluated by EM. EM is not typically performed on all BAL specimens
owing to uncertainties with specificity and sensitivity as well as
cost/benefit analyses. Because idiopathic pneumonias in our patient
population account for a large proportion of posttransplant
complications, we have elected to use EM in evaluating our BAL samples.
However, the routine use of EM should await results of clinical trials.

Although it is not routinely evaluated for, coronavirus should be
considered in the differential diagnoses of respiratory failure in
patients who have undergone high-dose chemotherapy and autologous BMT.

This work was supported by NIH grant HL55166 and the Duke Comprehensive
Cancer Center. Dr. Folz is a Parker B. Francis Fellow in Pulmonary
Research.

Figure Jump LinkFigure 1. Chronologic series of events leading up to the
coronavirus pneumonia. At the time points indicated (circles), the
absolute Dlco, corrected for hemoglobin concentration, was
measured.31 The patient’s predicted Dlco is
shown by a dashed line. The four cycles of adjuvant chemotherapy are
indicated by CAF and occurred at days −132, −103, −75, and −47.
XRT = external radiation therapy; HDC = high-dose chemotherapy.Grahic Jump Location

Acknowledgments

The authors acknowledge the assistance of Dr. Sara
Miller and the Duke University Electron Microscopy Virology Lab as well
as the physicians, nurses, and support staff of the Duke University
Bone Marrow Transplant Program. We thank Drs. William P. Petros and
Emily K. Folz for critical reading of this report.

Figures

Figure Jump LinkFigure 1. Chronologic series of events leading up to the
coronavirus pneumonia. At the time points indicated (circles), the
absolute Dlco, corrected for hemoglobin concentration, was
measured.31 The patient’s predicted Dlco is
shown by a dashed line. The four cycles of adjuvant chemotherapy are
indicated by CAF and occurred at days −132, −103, −75, and −47.
XRT = external radiation therapy; HDC = high-dose chemotherapy.Grahic Jump Location

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